Blood Eosinophil Count, Smoking Status Predict ICS Response in COPD

— IMPACT analysis shows value of continuous eosinophil modeling

Assessment of patient blood eosinophil count and smoking status may help optimize treatment with inhaled corticosteroids (ICS), a post-hoc analysis of the pivotal IMPACT trial found.

Prospective modeling of blood eosinophil count as a continuous measure, rather than a single cut-off eosinophil threshold, showed greater response to ICS in terms of exacerbation reduction with increasingly greater blood eosinophil count in patients with moderate-to-severe COPD with at least one exacerbation over the previous year, reported Steven Pascoe, MBBS, and colleagues.

Patient smoking status interacted with eosinophil count to predict ICS response, with former smokers more likely to benefit from treatment with ICS than current smokers, the authors wrote in the Lancet Respiratory Medicine.

The IMPACT trial was the largest study to date to examine the impact of single inhaler triple therapy with an inhaled corticosteroid, long-acting beta agonist (LABA), and long-acting muscarinic antagonist (LAMA), compared to dual therapy with a LAMA-LABA or ICS-LABA.

Compared to either dual therapy, triple therapy was found to reduce COPD exacerbations and improve both lung function and quality of life.

Pascoe, who now works in drug development for Sanofi but was formerly with IMPACT-funder GlaxoSmithKline, said in an interview with MedPage Today that the trial was originally designed to allow prospective analysis of the association between blood eosinophil count over time and ICS response, in an effort to better identify patients most likely to benefit from treatment with an inhaled corticosteroid.

"In this analysis we showed an incremental increase in benefit with increasing eosinophil count," he said, adding that this finding and the finding that smoking status also significantly impacted ICS response suggest that assessing multiple patient characteristics and a continuum of eosinophil counts will define personalized medicine in COPD.

"Where this is taking us is that the future is not just one biomarker and one (eosinophil) cut-off point," Pascoe added.

The researchers utilized fractional polynomials to continuously model patient blood eosinophil counts during the IMPACT trial, which originally included 10,355 participants. Negative binomial regression was used to determine the number of moderate-to severe exacerbations, severe exacerbations, and pneumonia.

The analysis showed a greater reduction in exacerbations at eosinophil counts higher than 100 cells per μL with triple therapy compared to LABA-LAMA and with ICS-LABA compared to LABA-LAMA.

Pneumonia risk was not associated with baseline eosinophil counts and smoking status had a direct impact on the ability of blood eosinophil count to predict ICS response.

"Smoking status modified the relationship between observed efficacy and blood eosinophil count for moderate or severe exacerbations, Transition Dyspnea Index and FEV1, with former smokers being more corticosteroid responsive at any eosinophil count that current smokers," Pascoe and colleagues wrote.

In an editorial published with the analysis, Maarten van den Berge, MD, and Huib Kerstjens, MD, both of the University of Groningen in The Netherlands, wrote that while the findings add support to the treatment guideline recommendations in GOLD 2019, they also present new information that should be incorporated in future GOLD recommendations.

"The continuous modelling by Pascoe and colleagues of the IMPACT data shows that the traditional way of considering blood eosinophils as a dichotomous variable is too simplistic," they wrote. "With increasing blood eosinophils, the benefits of adding ICS to LABA-LAMA or to LABA alone increase further in a continuous way, especially for exacerbations."

The post-hoc analysis findings also make a strong case for adding smoking status to the current list of patient symptoms and characteristics identified in GOLD 2019 for predicting ICS response, van den Berge and Kerstjens added.

They concluded that the IMPACT and similar KRONOS trial comparing fixed-dose triple therapy to dual therapy, "provide important new insights into the role of blood eosinophils as a continuous parameter to predict ICS treatment response in COPD."

"Increasing numbers of treatable traits and more detailed use of eosinophil counts (as a continuous variable) render personalized medicine increasingly feasible," the editorialists wrote. "Unfortunately, increasing numbers of traits and counts do render use of these data more complex for the practicing clinician. Web-based algorithms will be needed to define and make optimal treatment guidance, applicable for personalized patient advice and shared decisions. Such algorithms, however promising, should be tested prospectively."

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